1. Field of the Invention
The present invention relates to novel peptides that are capable of reducing blood pressure in a subject. More specifically, the present invention relates to novel peptides obtained from enzymatic hydrolysis of yellow pea seed proteins capable of lowering the blood pressure and reducing the effects of kidney disease in a subject by inhibiting or reducing the affinity of the enzymes in the renin-angiotensin system for their substrates, specifically renin.
2. Description of Related Art
Hypertension is a chronic disease which afflicts about 21% of the population of the United States (Cutler et al., 2008). Chronic hypertension can lead to Cardiovascular Disease (CVD) and Chronic Kidney Disease (CKD) which can be detected in 10% of the population (Kamper et al., 2009).
The renin-angiotensin system (RAS) plays a central role in the regulation of blood pressure and electrolyte metabolism (Oparil & Haber, 1974; Zaman, Oparil, & Calhoun, 2002). Renin is the first and rate-determining enzyme in RAS, catalyzing the hydrolytic release of Angiotensin I (Ang I) from the N-terminal end of angiotensinogen. Angiotensin 1 is subsequently converted into a potent pressor octapeptide, angiotensin II, by the angiotensin I-converting enzyme (ACE). ACE is one of the most extensively studied enzymes and its predominant physiological function in cardiovascular homeostasis is well documented (see for example Skeggs, Kahn, & Shumway, 1956). Blockade of Angiotensin II accumulation through the inhibition of ACE has been proven as a validated treatment approach for hypertension (Cushman & Ondetti, 1999). However, the long-term treatment by ACE inhibitors (ACEI) seems not to completely suppress the circulating renin-angiotensin system as plasma Angiotensin II (Ang II) and aldosterone levels tend to return toward pre-treatment values. The presence of non-RAS enzymes, including tonin and cathepsin, are capable to generate Ang II directly from angiotensinogen that contribute to the elevated Angiotensin II and aldosterone levels after ACEI treatment [Zaman, Oparil, & Calhoun, 2002]. ACE is an enzyme with broad substrates and inhibitors specificities (Acharya, Sturrock, Riordan, & Ehlers, 2003). In addition of the inhibition of conversion of Ang I into Ang II, ACEI also inhibits the degradation of bradykinin, which may be related to its side effects observed with ACE-inhibitory drugs such as the rare cases of angioneurotic edema and the more frequent occurrence of cough (Acharya, Sturrock, Riordan. & Ehlers, 2003; Slater et al 1988; Waeber, Nussberger, & Brunner, 1995).
Administering subjects with Angiotensin II Receptor Blockers (ARBs), which inhibit binding of Angiotensin II to the AT1 receptors, is a common alternative to use of ACE inhibitors to treat hypertension (Heran B S, Wong M M Y, Heran I K, & Wright J M, 2008). While ARBs are not responsible for degradation of bradykinin, they can still lead to angioedema (Abdi R, Dong VM, Lee CJ, & Ntoso K A, 2002). Further side effects associated with use of ARBs are a higher risk of myocardiac infarction (Varma S & Strauss M., 2004).
In contrast to ACE, renin is a highly specific enzyme, having angiotensinogen as its only known physiological substrate (Foltmann & Pedersen, 1977). Inhibiting renin at this step would be expected to block the classic RAS cascade, and therefore would have blood pressure lowering effect and avoid ACEI-related side effects (Haber, 1989). Although very attractive, unfortunately, research on renin inhibitors have been proven unsuccessful for clinical application due mainly to the lack of oral bioavailability or efficacy (Poulsen, Burton, & Haber, 1976; Haber 1986).
In view of the current state of the art, it would be advantageous to provide a compound and a method that: can effectively reduce high blood pressure, can be obtained from natural sources, can be delivered orally, can be capable of inhibiting renin and can be easy to manufacture, and that can overcome the current limitations to high blood pressure treatments, including common side effects and decreased efficacy over long term treatment.